Background:We studied the role of the mineralocorticoid receptor (MR) for atrial fibrotic remodeling. Results: Increased 11␤-hydroxysteroid dehydrogenase type 2 in atrial fibrillation enhances mineralocorticoid receptor profibrotic signaling through connective tissue growth factor, lysyl oxidase, and microRNA-21. Conclusion:The MR regulates fibrogenesis in atrial fibrillation. Significance: The MR may represent a target for the prevention of atrial fibrosis.

The aim of the study was to characterize the role of Rac1 GTPase for the mineralocorticoid receptor (MR)-mediated pro-fibrotic remodeling. Transgenic mice with cardiac overexpression of constitutively active Rac1 (RacET) develop an age-dependent phenotype with atrial dilatation, fibrosis, and atrial fibrillation. Expression of MR was similar in RacET and WT mice. The expression of 11β hydroxysteroid dehydrogenase type 2 (11β-HSD2) was age-dependently up-regulated in the atria and the left ventricles of RacET mice on mRNA and protein levels. Statin treatment inhibiting Rac1 geranylgeranylation reduced 11β-HSD2 up-regulation. Samples of human left atrial myocardium showed a positive correlation between Rac1 activity and 11β-HSD2 expression ( = 0.7169). Immunoprecipitation showed enhanced Rac1-bound 11β-HSD2 relative to Rac1 expression in RacET mice that was diminished with statin treatment. Both basal and phorbol 12-myristate 13-acetate (PMA)-induced NADPH oxidase activity were increased in RacET and correlated positively with 11β-HSD2 expression ( = 0.788 and = 0.843, respectively). In cultured H9c2 cardiomyocytes, Rac1 activation with l-buthionine sulfoximine increased; Rac1 inhibition with NSC23766 decreased 11β-HSD2 mRNA and protein expression. Connective tissue growth factor (CTGF) up-regulation induced by aldosterone was prevented with NSC23766. Cardiomyocyte transfection with 11β-HSD2 siRNA abolished the aldosterone-induced CTGF up-regulation. Aldosterone-stimulated MR nuclear translocation was blocked by the 11β-HSD2 inhibitor carbenoxolone. In cardiac fibroblasts, nuclear MR translocation induced by aldosterone was inhibited with NSC23766 and spironolactone. NSC23766 prevented the aldosterone-induced proliferation and migration of cardiac fibroblasts and the up-regulation of CTGF and fibronectin. In conclusion, Rac1 GTPase regulates 11β-HSD2 expression, MR activation, and MR-mediated pro-fibrotic signaling.

Heart rate data as produced by the subjects under investigation both in resting conditions and taken as total means per trial initially showed a trend towards ergotropic, clearly tachycardiac behavior; with the onset of thymoleptic drug therapy, there followed a further increase in heart rate, frequencies remaining more or less stationary on this level during the 26-day period observed by us. We found differences between morning and evening data of session A with 50 % of subjects, 25 % showing higher frequencies in their morning data, the reverse applying to a further 25 %. The remaining 50 % did not show any differences worth mentioning. At the end of the investigation period, the relation changed in favor of an increase in heart rate in the evening with 50 % of subjects, whereas only 12.5 % showed increased heart rate jn the morning; 37.5 % did not show significant differences. We could not demonstrate these results to be related to diurnal variation, degree of depression or course of the disease.

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